First-line ibrutinib plus venetoclax for nonblastoid mantle cell lymphoma in patients ≥65 years old or with TP53 mutations.

The phase 3 SYMPATICO study included an open-label cohort to evaluate first-line ibrutinib plus venetoclax in patients with nonblastoid mantle cell lymphoma (MCL) aged ≥65 years (n = 65) or ≥18 years with a TP53 mutation (TP53m; n = 11). Eligible patients received oral ibrutinib 560 mg once daily and venetoclax (5-week ramp-up to 400 mg once daily) for 2 years, then single-agent ibrutinib 560 mg until disease progression or unacceptable toxicity. In total, 78 patients were enrolled. With a median time on study of 40.5 months, the complete response (CR) rate was 69% (95% confidence interval [CI], 58-79), and the overall response rate was 95% (95% CI, 87-99). The median duration of response was 37.1 months (95% CI, 30.3 to not estimable [NE]). The median progression-free survival (mPFS) was 40.2 months (95% CI, 29.4 to NE); median overall survival (OS) was not reached (3-year OS rate, 79% [95% CI, 68-86]). In patients aged ≥65 years, CR rates were 76% (no TP53m) and 44% (with TP53m), mPFS was 40.2 and 22.0 months, and 3-year OS was 85% and 66%, respectively. In adult patients aged <65 years (with TP53m), the CR rate was 73%, mPFS was 15.4 months, and 3-year OS was 73%. The most common treatment-emergent adverse events were diarrhea (49%), fatigue (37%), neutropenia (35%), and COVID-19 (32%). First-line ibrutinib plus venetoclax showed promising efficacy, with high CR rates and durable remissions, in patients with previously untreated nonblastoid MCL and may be an option for patients aged ≥65 years or patients of any age with TP53m. The trial was registered at www.clinicaltrials.gov as NCT03112174.